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Wound-healing plasticity enables clonal expansion of founder progenitor cells in colitis.

Accepted version
Peer-reviewed

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Authors

Liu, Cambrian Y 
Girish, Nandini 
Gomez, Marie L 
Kalski, Martin 
Bernard, Jessica K 

Abstract

Chronic colonic injury and inflammation pose high risks for field cancerization, wherein injury-associated mutations promote stem cell fitness and gradual clonal expansion. However, the long-term stability of some colitis-associated mutational fields could suggest alternate origins. Here, studies of acute murine colitis reveal a punctuated mechanism of massive, neutral clonal expansion during normal wound healing. Through three-dimensional (3D) imaging, quantitative fate mapping, and single-cell transcriptomics, we show that epithelial wound repair begins with the loss of structural constraints on regeneration, forming fused labyrinthine channels containing epithelial cells reprogrammed to a non-proliferative plastic state. A small but highly proliferative set of epithelial founder progenitor cells (FPCs) subsequently emerges and undergoes extensive cell division, enabling fluid-like lineage mixing and spreading across the colonic surface. Crypt budding restores the glandular organization, imprinting the pattern of clonal expansion. The emergence and functions of FPCs within a critical window of plasticity represent regenerative targets with implications for preneoplasia.

Description

Keywords

Inflammatory bowel disease, epithelium, imaging, inflammation, intestine, lineage, regeneration, single-cell, stem cells, Mice, Animals, Colitis, Epithelial Cells, Stem Cells, Wound Healing

Journal Title

Dev Cell

Conference Name

Journal ISSN

1534-5807
1878-1551

Volume Title

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Wellcome Trust (203151/A/16/Z)
Wellcome Trust (219478/Z/19/Z)
Medical Research Council (MC_PC_17230)
This grant code will be add at the final proof stage Wound-healing plasticity enables clonal expansion of founder progenitor cells in colitis